Šimoničová Kristína, Janotka Ľuboš, Kavcová Helena, Sulová Zdena, Breier Albert, Messingerova Lucia
Institute of Molecular Physiology and Genetics, Centre of Biosciences, Dúbravská Cesta 9, Bratislava, 840 05, Slovakia.
Institute of Molecular Physiology and Genetics, Centre of Biosciences, Dúbravská Cesta 9, Bratislava, 840 05, Slovakia; Institute of Biochemistry and Microbiology, Faculty of Chemical and Food Technology, Slovak University of Technology in Bratislava, Radlinského 9, Bratislava, 812 37, Slovakia.
Drug Resist Updat. 2022 Mar;61:100805. doi: 10.1016/j.drup.2022.100805. Epub 2022 Jan 21.
Resistance to the hypomethylating agents (HMAs) 5-azacytidine (AZA) and 5-aza-2'-deoxycytidine (DAC) represents a major obstacle in the treatment of elderly patients with myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) which are not suitable for hematopoietic stem cells transplantation. Approximately 50 % of patients do not respond to HMA treatment because of intrinsic (primary) resistance, while others could acquire drug resistance during the repeated cycles of the treatment. To prevent, delay or surmount resistance development, the molecular mechanisms underlying drug resistance must be first identified. This is crucial as no further standard therapeutic opportunities are available for these patients who failed hypomethylating agents-based treatment. The current review provides an updated information about the different mechanisms that may contribute to the development of resistance to HMAs. Despite the similar structure and mechanism of action of HMA, several studies did not report the expected development of cross-resistance. It is clear that in addition to the common modalities of chemoresistance, there must be some specific mechanisms of drug resistance. Changes in transport and metabolism of HMAs are among the most studied mechanisms of resistance. Drug uptake provided by two solute carrier (SLC) families: SLC28 and SLC29 (also known as the concentrative and equilibrative nucleoside transporter families, respectively), could represent one of the mechanisms of cross-resistance. Changes in the metabolism of these drugs are the most likely mechanism responsible for the unique mode of resistance to AZA and DAC. Deoxycytidine kinase and uridine-cytidine kinase due to their necessity for drug activation, each could represent one of the response markers to treatment with DAC and AZA, respectively. Other mechanisms involved in the development of resistance common for both drugs involved: i. increased DNA repair (caused for example by constitutive activation of the ATM/BRCA1 pathway and inhibition of p53-dependent apoptosis); ii. changes in the regulation of apoptosis/disrupted apoptotic pathways (specifically increased levels of the anti-apoptotic protein BCL2) and iii. increased resilience of leukemic stem cells to multiple drugs including HMAs. Despite intense research on the resistance of MDS and AML patients to HMAs, the mechanisms that may reduce the response of these cells to HMAs are not known in detail. We herein highlight the most important directions that future research should take.
对低甲基化药物（HMAs）5-氮杂胞苷（AZA）和5-氮杂-2'-脱氧胞苷（DAC）产生耐药性是治疗不适用于造血干细胞移植的老年骨髓增生异常综合征（MDS）和急性髓系白血病（AML）患者的主要障碍。约50%的患者因内在（原发性）耐药而对HMA治疗无反应，而其他患者可能在重复治疗周期中获得耐药性。为了预防、延缓或克服耐药性的产生，必须首先确定耐药的分子机制。这一点至关重要，因为对于这些基于低甲基化药物治疗失败的患者，没有进一步的标准治疗机会。本综述提供了有关可能导致对HMAs耐药性产生的不同机制的最新信息。尽管HMA的结构和作用机制相似，但多项研究并未报告预期的交叉耐药性发展情况。显然，除了常见的化疗耐药模式外，必然存在一些特定的耐药机制。HMAs转运和代谢的变化是研究最多的耐药机制之一。由两个溶质载体（SLC）家族提供的药物摄取：SLC28和SLC29（分别也称为浓缩型和平衡型核苷转运体家族），可能是交叉耐药的机制之一。这些药物代谢的变化是对AZA和DAC独特耐药模式最可能的机制。脱氧胞苷激酶和尿苷-胞苷激酶由于它们对药物激活的必要性，分别可能是对DAC和AZA治疗反应的标志物之一。两种药物耐药性产生所涉及的其他共同机制包括：i. DNA修复增加（例如由ATM/BRCA1途径的组成性激活和p53依赖性凋亡的抑制引起）；ii. 凋亡调节/凋亡途径破坏的变化（特别是抗凋亡蛋白BCL2水平升高）；iii. 白血病干细胞对包括HMAs在内的多种药物的耐受性增加。尽管对MDS和AML患者对HMAs的耐药性进行了深入研究，但这些细胞对HMAs反应降低的机制仍不清楚。我们在此强调了未来研究应采取的最重要方向。
